How to treat VEXAS syndrome: a systematic review on effectiveness and safety of current treatment strategies

Lara D. Veeken, Journal Year: 2023, Volume and Issue: 62(11), P. 3518 - 3525

Published: May 26, 2023

Abstract Objectives To evaluate the effectiveness and safety of current treatment strategies for vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic (VEXAS) syndrome. Methods A protocolized systematic review according to Preferred Reporting Items Systematic Reviews Meta-Analyses (PRISMA) guidelines was performed. Three databases were searched reports on VEXAS. Data from included publications extracted a narrative synthesis Treatment response recorded as complete (CR), partial (PR) or none (NR) depending changes in clinical symptoms laboratory parameters. Patient characteristics, data previous treatments analysed. Results We identified 36 with total 116 patients; 113 (98.3%) male. The azacytidine (CR 9/36, 25%; PR 14/36, 38.9%), Janus kinase inhibitors (JAKi) 11/33, 33%; 9/33, 27.3%), tocilizumab 3/15, 20%; 6/15, 40%), allogeneic stem cell transplantation 6/7, 85.7%; one patient died), anakinra 4/5, 80%; NR 1/5, 20%), canakinumab 1/2, 50%; 50%) glucocorticoid monotherapy 1/6, 16.7%; 4/6, 66.7%). Individual available TNF inhibitors, rituximab MTX. adverse events 67 patients (67/116, 57.8%) included: pneumonia (12/67, 17.9%), other infections (9/67, 13.4%), venous thromboembolisms (6/67, 8.9%), cytopenias (4/67, 5.9%), acute 5.9%) chronic graft-vs-host-disease (2/67, 2.9%). Conclusion Current VEXAS are limited inhomogeneous. decisions should be individualized. For devolvement algorithms trials needed. Adverse remain challenge, especially an elevated risk thromboembolism associated JAKi carefully considered.

Language: Английский

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Allogeneic hematopoietic cell transplantation for VEXAS syndrome: results of a multicenter study of the EBMT

Blood Advances, Journal Year: 2024, Volume and Issue: 8(6), P. 1444 - 1448

Published: Feb. 8, 2024

Language: Английский

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Autoimmune manifestations in VEXAS: Opportunities for integration and pitfalls to interpretation

Journal of Allergy and Clinical Immunology, Journal Year: 2023, Volume and Issue: 151(5), P. 1204 - 1214

Published: March 21, 2023

VEXAS (Vacuoles, E1 enzyme, X-linked, Autoinflammatory, Somatic) is a novel entity manifesting with multiplicity of clinical features. Somatic mutations the UBA1 gene in hematopoietic stem cells constitute genetic basis VEXAS. As an X-linked disorder, most cases occur men, classically developing symptoms during fifth to sixth decade life. Considering its multidisciplinary nature involving numerous branches internal medicine, has elicited wide medical interest and several conditions have been associated this disease. Even so, recognition everyday practice not necessarily straightforward. Close collaboration between different specialists mandatory. Patients may manifest range features from manageable cytopenias disabling life-threatening autoimmune phenomena limited responses therapy, potential for progression hematological malignancies. Diagnostic treatment guidelines are exploratory include rheumatological supportive care treatments. Allogeneic cell transplantation potentially curative, but risks significant position algorithm yet be defined. Herein, we present variegated manifestations VEXAS, provide criteria diagnostic testing UBA1, discuss options, including allogeneic transplantation, current evidence, future directions.

Language: Английский

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VEXAS syndrome: complete molecular remission after hypomethylating therapy

Annals of Hematology, Journal Year: 2024, Volume and Issue: 103(3), P. 993 - 997

Published: Jan. 12, 2024

Abstract The VEXAS syndrome, a genetically defined autoimmune disease, associated with various hematological neoplasms has been attracting growing attention since its initial description in 2020. While therapeutic strategies have explored case studies, the optimal treatment strategy is still under investigation and allogeneic cell transplantation considered only curative treatment. Here, we describe 2 patients who achieved complete molecular remission of underlying UBA1 mutant clone outside context HCT. Both received hypomethylating agent azacitidine, deep triggered de-escalation even cessation sustained one them. Prospective studies are necessary to clarify which will benefit most from therapy understand variability response different strategies.

Language: Английский

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Skin Manifestations of VEXAS Syndrome and Associated Genotypes

JAMA Dermatology, Journal Year: 2024, Volume and Issue: 160(8), P. 822 - 822

Published: June 12, 2024

Importance VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome is a newly defined genetic disease with an estimated prevalence of 1 in 4269 men older than 50 years and marked by systemic inflammation, progressive bone marrow failure, inflammatory cutaneous manifestations. Objective To define the spectrum manifestations association these findings clinical, genetic, histological features. Design, Setting, Participants This observational cohort study included data from 112 patients who were diagnosed VEXAS-defining variants UBA1 between 2019 2023. Data collected medical record review or directly evaluated at National Institutes Health Bethesda, Maryland. Main Outcomes Measures histological, other clinical findings. A secondary outcome was response to treatment VEXAS. Results Among (median [range] age, 69 [39-79] years; 111 [99%] male), skin involvement common (93 [83%]), most frequent presenting feature (68 [61%]). Of 64 histopathologic reports available 60 patients, predominant leukocytoclastic vasculitis (23 [36%]), neutrophilic dermatosis (22 [34%]), perivascular dermatitis (19 [30%]). Distinct pathogenic associated specific The p.Met41Leu variant frequently dermal infiltrates (14 17 [82%]), often resembling histiocytoid Sweet syndrome. In contrast, p.Met41Val vasculitic lesions (11 20 [55%]) mixed leukocytic infiltrate (17 [85%]). Oral prednisone improved 67 73 (92%). Patients treated anakinra developed severe injection-site reactions (12 16 [75%]), including ulceration (2 12 [17%]) abscess formation (1 [8%]). Conclusions Relevance this show that are early manifestation Genetic evaluation for should be considered male vasculitis, dermatoses, chondritis. Awareness among dermatologists critical facilitate diagnosis.

Language: Английский

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De-escalation of corticosteroids and clonal remission in UBA1 mutation-driven VEXAS syndrome with 5-azacytidine

Haematologica, Journal Year: 2024, Volume and Issue: unknown

Published: June 13, 2024

Not available.

Language: Английский

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Diagnostic capabilities, clinical features, and longitudinal UBA1 clonal dynamics of a nationwide VEXAS cohort

American Journal of Hematology, Journal Year: 2023, Volume and Issue: 99(2), P. 254 - 262

Published: Dec. 18, 2023

Abstract VEXAS is a prototypic hemato‐inflammatory disease combining rheumatologic and hematologic disorders in molecularly defined nosological entity. In this nationwide study, we aimed at screenshotting the current diagnostic capabilities clinical‐genomic features of VEXAS, tracked UBA1 longitudinal clonal dynamics upon different therapeutics, including allogeneic hematopoietic cell transplant. We leveraged collaboration between Italian Society Experimental Hematology Rheumatology disseminated national survey to collect clinical molecular patient information. Overall, 13/29 centers performed genomic testing locally, Sanger sequencing (46%), next‐generation (23%), droplet digital polymerase chain reaction (8%), or combination (23%). A total 41 male patients were identified, majority (51%) with threonine substitutions Met41 hotspot, followed by valine leucine (27% 8%). Median age diagnosis was 67 years. All displayed anemia (median hemoglobin 9.1 g/dL), macrocytosis. Bone marrow vacuoles observed most cases (89%). The common association polychondritis (49%). concomitant myelodysplastic neoplasm/syndrome (MDS) diagnosed 71% ( n = 28), chiefly exhibiting lower Revised International Prognostic Scoring System risk profiles. Karyotype normal all patients, except three MDS showing ‐Y, t(12;16)(q13;q24), +8. frequently mutated gene DNMT3A 10), TET2 3). At last follow‐up, five died two progressed acute leukemia. Longitudinal demonstrated mutational clearance following collected interdisciplinary cohort, characterized heterogeneous manifestations treatments used. cases. Patients exhibited various dynamics.

Language: Английский

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New scenarios in Vacuoles, E1 enzyme, X linked, Autoinflammatory, Somatic (VEXAS) syndrome: Evolution from myelodysplastic syndrome to acute myeloid leukemia

Current Research in Translational Medicine, Journal Year: 2023, Volume and Issue: 71(2), P. 103386 - 103386

Published: Feb. 26, 2023

Language: Английский

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Long‐term genetic and clinical remissions after cessation of azacitidine treatment in patients with VEXAS syndrome

HemaSphere, Journal Year: 2024, Volume and Issue: 8(8)

Published: July 30, 2024

VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) is an inflammatory syndrome caused by acquired mutations in the gene encoding ubiquitin like modifier activating enzyme 1 (UBA1) that often fatal.1, 2 Allogeneic hematopoietic stem cell transplantation currently considered only curative treatment modality.3-6 We were first to report eradication of virtually all UBA1-mutated cells hypomethylating agent azacitidine, reflected clinical and genetic remissions,7 a finding confirmed recent phase II trial.8 Here, we persistent, long-term (11–84 months) remissions patients responding with after cessation therapy. The data indicate azacitidine may be attractive alternative transplant for disease reveal clonal stability under homeostatic conditions. Since its description December 2020,1 UBA1 variant-confirmed diagnosis was made 11 at our institution until February 2024 (all male, median age 67 years, range 57–77 years). mutation detection panel-based sequencing these performed as previously reported7 described Supporting Information Methods section. Of patients, eight have been exposed (administered dose 75 mg/m2 subcutaneously once daily 7 days 4-weekly schedule). three not two treated corticosteroids deceased due infectious complications, one patient candidate psychosocial circumstances. In used last resort on in-house basis, failure multiple other lines treatment, time critically ill (WHO performance status 4) VEXAS-related (respiratory) pathology. Both died shortly administration cycle clinically active disease, before assessment response cycle. Six received cycles (range, 3–8 cycles) out-patient basis monitoring response. characteristics six are listed Table 1. Patients carried concurrent DNMT3A variant allele frequency (VAF) 59% 30%, respectively, 3 TET2 VAF 4%. 4, 5, 6 no detected sequencing. Three us before, including whom retrospect, is, azacitidine.7 Long-term follow-up initial reported here. study compliance Declaration Helsinki, gave informed consent participation. All because they suffered from frequent (life-threatening) flares (in but 4 5 transfusion-dependent) anemia, insufficiently disease-modifying antirheumatic drugs (DMARDs) and/or biologicals (specified 1) requiring corticosteroid concomitant adverse events. note, four formally fulfilled MDS criteria according WHO 2016 classification, based presence cytopenia (anemia Hb <10 g/dL) dysplasia (≥10% any lineage), clonality demonstrated mutational analyses patients. Five (5/6) achieved azacitidine. causative decreased 67% (range 56%–86%) bone marrow or peripheral blood start (indicating majority mutation) ≤1% 0%–1%), which documented five out 1, retrospective firstly cycles). 1% 30% 2%, consistent notion resulted carrying both variants Genetic remissions, indicative dramatic reduction number cells, associated complete defined absence normalization C-reactive protein (CRP) plasma increase hemoglobin levels (Figure 1). immuno-modulatory (e.g., corticosteroids, DMARDs tocilizumab) could weaned evaluation achieving response, characteristic vacuolisation erythroid myeloid precursor erythroid, megakaryocytic lineages, disappeared. nonresponder (patient 3) total mutant remained high (VAF 84%). similar (4% 3%, respectively). Quality life anemia had improved. Clinical symptoms relatively mild stopped, retrospect might too early achieve remission. stopped arbitrarily < 5%. this done colon carcinoma, decision interrupt/stop upon grade 2–3 effects (fatigue neutropenia) observation maintained drug cessation. remaining genetically-defined 75% 0% 56% 6) recently (at submission manuscript, May 2024) discontinued fifth previous experience immunomodulatory (as specified completely except who continues prednisolone mg VEXAS-unrelated reasons. After present) remission current follow up 31 months 11–84 remain free manifestations maintain stable normalized levels. 0%–7%) during years. did observe very gradual (from 7%) over course further interest, notably affected episodes Campylobacter jejuni PCR-positive gastro-enteritis hospitalization episode crystal proven gout 2) Collectively, findings confirm rates syndrome, others,7-10 and, more importantly, safely achievement resulting remissions. This significant relevance it would position available eradicating therapeutic approach Furthermore, safeguard frequently occurring drug, fatigue, myelosuppression affecting quality life. warrant incorporation interruption ("holiday") designs future prospective trials investigating value syndrome. mechanism eradicates known date, hypothesized defect ubiquitin-proteasome system sensitizes agent. Finally, shed new light biology kinetics clones, demonstrating can many even elderly Although small draw conclusions, suggest clones "homeostatic" conditions also event "inflammatory stress" It speculated evolution takes years ultimately, UBA1-driven inflammation, above critical threshold, feed-forward manner. Breaking loop (with azacitidine) thus result awaits experimental support Marc H. G. P. Raaijmakers conceived supervised study. Anna M. Aalbers responsible care collected data, wrote manuscript. Paul L. A. van Daele Virgil S. Dalm edited Peter J. Valk coordinated authors declare conflict interest. research funding. corresponding author reasonable request. Please note: publisher content functionality supporting information supplied authors. Any queries (other than missing content) should directed article.

Language: Английский

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VEXAS Syndrome—Review

Global Medical Genetics, Journal Year: 2023, Volume and Issue: 10(03), P. 133 - 143

Published: July 10, 2023

Abstract VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome is a newly defined refractory adult-onset autoinflammatory caused by somatic mutations in the ubiquitin-like modifier-activating enzyme 1 (UBA1) gene hematopoietic stem and progenitor cells, resulting shift UBA1 isoform expression. Thus, patients develop spectrum of systemic inflammatory manifestations hematologic symptoms. To date, respond poorly to immune suppressive drugs, except high-dose glucocorticoids, no treatment guidelines have been established. Given high mortality rate, needs be taken seriously physicians all specialties. This article aims describe key features, pathogenesis, clinical better understand targeted improve prognosis syndrome.

Language: Английский

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